Dementia is a disease usually accompanied by several complex cognitive disorders, such as memory loss, degeneration of intelligence, personality changes, abnormal behavior, etc. This syndrome is a cerebral degenerative disease, one of the brain diseases of the central nervous system (CNS). In this syndrome, the continuous apoptosis of neural cells induces degenerative CNS diseases, which in turn results in irreversible dysfunction of the neural network and permanent damages in corresponding functions of the body. The cerebral degenerative diseases induce apoptosis of general or specific neural cells. However, since there is no regenerative potential in differentiated neural cells, the apoptosis of neural cells results in irreversible impairment of cerebral functions.
Most therapeutic agents for Alzheimer's dementia are inhibitors for acetylcholinesterase, an enzyme that degrades acetylcholine esters. Examples include, but not limited to, donepezil (Aricept™), rivastigmin (Exelon™), galantamine (Reminyl™) and others. Among the acetylcholinesterase inhibitors, donepezil was approved for patients with dementia by the United States Food and Drug Administration (FDA) in 1996, and has been used for treating mild and moderate or severe Alzheimer's dementia. Reversible inhibition by donepezil of the acetylcholine degrading enzymes (e.g., acetylcholinesterase and butyrylcholinesterase) increases the amount of acetylcholine in the Alzheimer patients' brains, thereby activating cholinergic neurons (neurons which primarily use acetylcholine as a neurotransmitter).
Commercial formulations of donepezil have been marketed as a tablet, which is orally administered to patients suffering from Alzheimer's dementia. However, it has been reported that it is impossible for these oral formulations of donepezil to avoid the hepatic first-pass effect, and furthermore these oral dosage forms are known to produce gastrointestinal side effects such as indigestion, diarrhea, GI irritation, and others. Furthermore, patients suffering from fairly advanced dementia typically have difficulty complying with an oral dosage regimen.
U.S. Patent Publication No. 2004/0258741 and Korean Patent Publication Patent No. 10-2005-0037405, hereby incorporated by reference, teach transdermal delivery systems based on a synthetic rubber polymer such as styrene-isoprene-styrene (SIS) and/or polyisobutylene (PIB). However, since this transdermal delivery system displayed a relatively low skin penetration rate of donepezil, it was manufactured so as to have a very large surface area in order to overcome this limitation. As a result of the large size of this delivery system, patients' compliance may be decreased when the transdermal delivery system is applied to patients for 1 to 2 days through single application. In addition, if the drug concentration in the matrix of the transdermal delivery system is more than 8%, a crystalline solid is formed, which may decrease the adhesive force, lead to a non-uniform skin penetration rate of the active agent, and create storage problems, resulting in difficulty maintaining the drug therein in a high concentration.
In addition, U.S. Patent Publication Nos. 2010/0080842, 2008/0138388, and 2009/0175929, hereby incorporated by reference, teach a transdermal delivery system obtained by using an acrylic pressure-sensitive adhesive having a carboxylic acid functional group or hydroxyl functional groups, as well as using a specific absorption enhancer or a specific crystalline donepezil (a Form-B crystal) or a specific crystallization-inhibiting agent (a methacrylate copolymer having a carboxyl group). However, if an acrylic adhesive is used as a matrix of the transdermal delivery system, the drug diffusion is slowed in the pressure-sensitive adhesive layer due to the interaction between donepezil and the acrylic polymer in the layer, which also reduce movement of the drug from the pressure-sensitive adhesive layer to the skin. In order to solve this problem, Korean Patent Publication No. 10-2009-0101667, hereby incorporated by reference, has disclosed a transdermal delivery system obtained by using an EVA (ethylene vinyl acetate) adhesive and a rosin ester resin as a crystallization-inhibiting agent.
In addition, International Patent Application Publication No. WO 2011/049038, hereby incorporated by reference, discloses transdermal drug delivery system obtained by dissolving the active agent, donepezil, in an adhesive containing a styrene-isoprene-styrene block copolymer, a hydrogenated rosin glycerol ester, liquid paraffin, and an absorption enhancer. However, this transdermal drug delivery system resulted in unsatisfactory side effects such as moderate to severe skin irritation. Dementia is a chronic disease requiring application of the transdermal patch for long time. Moderate to severe skin irritation would drop the patient's compliance significantly and it would be difficult to achieve any effective treatment. Furthermore, if any use of skin irritating material, such as absorption enhancer, is eliminated from the transdermal drug delivery system to minimize the skin irritation, there is another problem such as that the skin penetration will be reduced significantly.